RESEARCH—HUMAN—CLINICAL STUDIES RESEARCH—HUMAN—CLINICAL STUDIES
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Minocycline Prevents Focal Neurological Deterioration Due to Cerebral Hyperperfusion After Extracranial-Intracranial Bypass for Moyamoya Disease Miki Fujimura, MD*‡ Kuniyasu Niizuma, MD* Takashi Inoue, MD‡ Kenichi Sato, MD* Hidenori Endo, MD* Hiroaki Shimizu, MD* Teiji Tominaga, MD* *Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan; ‡Department of Neurosurgery, National Hospital Organization, Sendai Medical Center, Sendai, Japan Correspondence: Miki Fujimura, MD, PhD, Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1.1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. E-mail: [email protected] Received, August 6, 2013. Accepted, October 25, 2013. Published Online, October 30, 2013. Copyright © 2013 by the Congress of Neurological Surgeons
BACKGROUND: Cerebral hyperperfusion (CHP) is a potential complication of superficial temporal artery–middle cerebral artery (STA-MCA) anastomosis for moyamoya disease (MMD), and optimal postoperative management has not yet been established. Minocycline, a neuroprotective antibiotic agent, plays a role in blocking matrix metalloproteinase 9 (MMP-9), which contributes to edema formation and hemorrhagic conversion after cerebral ischemia-reperfusion. Patients with MMD have been shown to have increased serum MMP-9 levels. OBJECTIVE: To examine the effect of minocycline on the prevention of postoperative CHP after STA-MCA anastomosis for MMD. METHODS: N-isopropyl-p-[123I]iodoamphetamine single-photon emission computed tomography was performed 1 and 7 days after STA-MCA anastomosis on 109 hemispheres in 86 consecutive patients with MMD (ages, 9-69 years; mean, 37.2 years). Postoperative systolic blood pressure was strictly maintained at lower than 130 mm Hg in all 109 surgeries. The most 60 recent hemispheres were managed by the intraoperative and postoperative intravenous administration of minocycline hydrochloride (200 mg/d). The incidence of focal neurological deterioration (FND) due to CHP was then compared with that in 36 patients undergoing 49 surgeries managed without minocycline. RESULTS: FND due to CHP was observed in 4 operated hemispheres in patients treated without minocycline (4/49, 8.16%), and in none in the minocycline-treated group (0/60) (P = .0241). Multivariate analysis revealed that minocycline administration (P , .001), surgery on the left hemisphere (P = .031), and a smaller recipient artery diameter (P , .001) significantly correlated with FND due to CHP. CONCLUSION: The administration of minocycline with strict blood pressure control may represent secure and effective postoperative management to prevent symptomatic CHP after STA-MCA anastomosis for MMD. KEY WORDS: Cerebral hyperperfusion, Extracranial-intracranial bypass, Minocycline hydrochloride, Moyamoya disease, Surgical complication Neurosurgery 74:163–170, 2014
DOI: 10.1227/NEU.0000000000000238
ABBREVIATIONS: CBF, cerebral blood flow; CHP, cerebral hyperperfusion; EC-IC, extracranialintracranial; EDMS, encephaloduromyosynangiosis; FND, focal neurological deterioration; 123I-IMPSPECT, N-isopropyl-p-[123I]iodoamphetamine singlephoton emission computed tomography; MCA, middle cerebral artery; MMD, moyamoya disease; MMP-9, matrix metalloproteinase 9; MRA, magnetic resonance angiography; SPECT, single-photon emission computed tomography; STA-MCA, superficial temporal artery–middle cerebral artery
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M
oyamoya disease (MMD) is a chronic, occlusive cerebrovascular disease of unknown etiology characterized by bilateral steno-occlusive changes at the terminal portion of the internal carotid artery and an abnormal vascular network at the base of the brain.1,2 The extracranial-intracranial (EC-IC) bypass such as superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis is generally used as the standard surgical treatment for MMD to prevent cerebral ischemic attacks.2-5
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Despite its favorable long-term outcome, increasing evidence suggests that focal cerebral hyperperfusion (CHP) is a cause of transient focal neurological deterioration (FND)6-15; however, optimal management remains undetermined. We previously showed that prophylactic blood pressure lowering during the early perioperative period reduced the risk of symptomatic CHP in patients with MMD,16 whereas excessive blood pressure lowering is still controversial because of the risk of ischemic complications at contralateral and/or remote areas. The expression of extracellular matrix proteins including matrix metalloproteinase 9 (MMP-9), which may play a role in degrading the endothelial basal lamina, an important structure in the bloodbrain barrier, by digesting type IV collagen, was shown to be higher in patients with MMD.17,18 MMP-9 is known to participate in edema formation and hemorrhagic conversion after cerebral ischemia-reperfusion injury.19,20 Because of the higher incidence of postoperative CHP in moyamoya patients than in atherosclerotic patients,11 it is conceivable that the increased expression of MMP-9 may contribute in part to CHP in patients with MMD. Because minocycline hydrochloride may play a role in blocking MMP-921 and is also known to have a neuroprotective effect against ischemic brain injury,22,23 we sought to determine whether the effect of minocycline, in addition to prophylactic blood pressure lowering, further reduced the risk of postoperative CHP after STA-MCA anastomosis for MMD.
PATIENTS AND METHODS Inclusion Criteria of Patients The correlation between postoperative changes in cerebral blood flow (CBF) and clinical course was investigated in 86 consecutive patients with MMD (male/female = 24/62; 9-69 years of age; mean, 37.2 years) surgically treated in 109 hemispheres by the same surgeon (M.F.) between January 2008 and June 2013. Inclusion criteria of this study, which corresponded to our surgical indications for STA-MCA anastomosis,11 included all of the following: the presence of ischemic symptoms (minor completed stroke and/or transient ischemic attack [TIA]), apparent hemodynamic compromise on single-photon emission computed tomography (SPECT) as defined in the following, independent activity of daily living (modified Rankin Scale scores of 0-2), and the absence of major cerebral infarction that exceeds the vascular territory of 1 major branch of the middle cerebral artery (MCA). All hemispheres that did not match these criteria were excluded from surgery. This study included 5 patients with a history of hemorrhage in whom 5 hemispheres were operated on. All 5 patients simultaneously had TIA or cerebral infarction on the affected hemispheres before surgery, which matched our indication for surgery. Preoperative CBF was quantified by the autoradiographic method in most cases, and CBF in each subregion was automatically calculated by 3-dimensional stereotactic region of interest template) software (version 2) provided by Daiichi Radio-Isotope (Tokyo, Japan) using N-isopropylp-[123I]iodoamphetamine single-photon emission computed tomography (123I-IMP-SPECT).11 The cerebral perfusion reserve capacity was quantified by the administration of acetazolamide. When CBF at rest was less than 80% of normal CBF (42 mL/100 g/min) and/or reactivity to acetazolamide was less than 10%, we regarded the CBF state as hemodynamic compromise. To avoid ischemic complications during examination,
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patients with crescendo TIA did not participate in the preoperative quantitative CBF study, only qualitative 123I-IMP-SPECT without acetazolamide stress testing. Most of the pediatric patients did not participate in preoperative 123I-IMP-SPECT with acetazolamide stress testing to avoid ischemic complications. One adult patient with progressing stroke underwent qualitative 123I-IMP-SPECT without acetazolamide stress testing only before surgery. Once hemodynamic compromise was confirmed, patients underwent revascularization surgery. All patients underwent STA-MCA (M4) anastomosis with encephaloduromyosynangiosis (EDMS).11 Patients were maintained under the conditions of normovolemia and normocapnia, whereas intraoperative systolic blood pressure was strictly maintained at less than 130 mm Hg during surgery by intravenous anesthesia using propofol.16 Craniotomy was performed around the sylvian fissure end, approximately 8 cm in diameter, and the stump of STA was anastomosed to the M4 segment of the MCA, which was followed by EDMS. To avoid postoperative compression of the brain surface by the swollen temporal muscle used for EDMS, we drilled out the inner layer of the bone flap and made a relatively wide bone window at the side of the EDMS graft insertion. All patients satisfied the diagnostic criteria of the Research Committee on Spontaneous Occlusion of the Circle of Willis of the Ministry of Health, Labor, and Welfare, Japan,2 except for 4 patients with “probable MMD” showing unilateral involvement.
Postoperative CBF Measurement and Diagnosis of Hyperperfusion CBF was routinely measured by 123I-IMP-SPECT 1 and 7 days after surgery in all patients. Postoperative computed tomography scans were routinely performed immediately after surgery and 1 day after surgery in all cases. Magnetic resonance imaging (MRI), 1.5 or 3T, and magnetic resonance angiography (MRA) were routinely performed within 3 days of surgery. MRI included diffusion-weighted images, T2-weighted images, and T2*-weighted images in all cases. Fluid-attenuated inversion recovery was also performed in most cases. The diagnostic criteria for symptomatic CHP11,16 included all of the following: (1) the presence of a significant focal increase in CBF, which was confined to the vascular territory of 1 major branch of the MCA at the site of the anastomosis, which was responsible for the apparent focal neurological signs; (2) apparent visualization of the STA-MCA bypass by MRA and the absence of any ischemic changes on diffusion-weighted images; and (3) the absence of other pathologies such as compression of the brain surface by the temporal muscle inserted for indirect pial synangiosis, ischemic attack, venous infarction, and CBF increases secondary to seizure. In addition to these items, blood pressure–dependent aggravation of symptoms and/or the amelioration of symptoms by blood pressure lowering clinically confirmed the diagnosis of symptomatic CHP. The occurrence of symptomatic CHP after revascularization surgery was evaluated by 123I-IMP-SPECT in the acute stage. We investigated the correlation between postoperative CBF changes and FND due to CHP in the 2 groups.
Postoperative Management All 86 patients with 109 hemispheres operated on were prospectively subjected to prophylactic intensive blood pressure control (,130 mm Hg systolic blood pressure) according to the standardized postoperative management protocol to prevent symptomatic CHP using a 1 to 10 mg/h continuous intravenous drip infusion of nicardipine hydrochloride, as previously described.16 Among them, 36 patients undergoing
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MINOCYCLINE TO PREVENT CEREBRAL HYPERPERFUSION
revascularization surgery for 49 hemispheres were managed by the routine prophylactic use of ampicillin-sulbactam (3.0 g/d) for 4 days, between January 2008 and July 2010. During the most recent period (between August 2010 and June 2013), 50 patients underwent revascularization surgery for 60 hemispheres and were managed by the intraoperative and postoperative intravenous administration of minocycline hydrochloride (200 mg/d) instead of ampicillin-sulbactam until 4 days after surgery to avoid the deleterious effects of CHP and reduce the potential risk of cerebral ischemia at remote areas. The protocol for the use of minocycline hydrochloride was approved by the Ethics Committee in our institution. Patients in whom symptomatic CHP developed underwent further blood pressure lowering. To avoid the unfavorable effect of intensive blood pressure lowering on the contralateral hemisphere and/or ipsilateral remote areas, we sought to maintain systolic blood pressure between 110 and 130 mm Hg, and we routinely administered antiplatelet agents (aspirin 100 mg/d or cilostazol 200 mg/d) starting the day after surgery in both periods. Based on the temporal profile of 123I-IMP-SPECT and MRI/ MRA findings, we gradually allowed a return to normotensive conditions within 7 to 10 days after surgery. If 123I-IMP-SPECT performed 1 day after surgery suggested focal hyperperfusion, we maintained strict blood pressure control at between 110 and 130 mm Hg or between 100 and 120 mm Hg, according to the severity of hyperperfusion, for 7 to 14 days after revascularization surgery.16
Statistical Analysis The incidence of FND due to CHP was compared between the minocycline-treated group and non–minocycline-treated group using logistic regression analysis. Correlations between focal neurological signs due to CHP and others factors including patient age, sex, side of the hemisphere operated on, type of onset (hemorrhagic onset), diameter of the recipient artery, and temporary occlusion time were also analyzed using a univariate logistic regression model. Multivariate statistical analysis of factors related to the development of symptomatic CHP, including the administration of minocycline, was performed using a logistic regression model. Systolic blood pressure 1 day after surgery was compared between the 2 groups by the Student t test. The incidence of CHP detected by SPECT, both symptomatic and asymptomatic, was also compared between the 2 groups by the x2 test.
RESULTS Overall Results Among the 86 consecutive patients with 109 surgeries, 4 patients (4 hemispheres, 3.67% of 109 operated hemispheres) exhibited temporary FND due to postoperative focal CHP 2 to 14 days after surgery (Table 1). All 4 patients were treated without minocycline. Postoperative MRI/MRA showed no ischemic changes, and the thick high signal of STA on the hemisphere operated on was evident in all 4 hemispheres. Postoperative SPECT revealed a significant increase in CBF at the sites of anastomosis in all 4 hemispheres. The anatomic location and temporal profile of hyperperfusion were consistent with the transient focal neurological signs in these 4 patients. The symptoms observed in all 4 cases fluctuated in a blood pressure–dependent manner, which further supported the diagnosis of symptomatic hyperperfusion. The symptoms of hyperperfusion were relieved by further blood
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TABLE 1. Incidence of Focal Neurological Deficit Due to Hyperperfusion After Extracranial-Intracranial Bypass
Hemisphere, no. (patients, no.) Age, y, range (mean) Male/female, no. Left/right, no. Focal neurological deficit due to hyperperfusion, no. (%) a
Minocycline Group
Non-Minocycline Group
60 (50) 10-66 (39.4) 11/39 30/30 0/60 (0)a
49 (36) 9-69 (35.9) 13/23 24/25 4/49 (8.16)
Significantly lower (P = .024).
pressure lowering with the free radical scavenger edaravone (Mitsubishi Pharma Co, Tokyo, Japan), although in 1 patient in the non–minocycline-treated group cerebral infarction in the ipsilateral occipital lobe developed during blood pressure lowering, which has been described as the representative case. FND due to CHP developed in none of the minocycline-treated patients. No adverse effect was reported for minocycline after 60 surgeries perioperatively managed with minocycline. Comparison of the Minocycline-Treated Group and Non–Minocycline-Treated Group Univariate Analysis As shown in Table 1, the incidence of FND due to CHP was significantly lower in minocycline-treated patients (0/60, 0%) than in patients treated without minocycline (4/49, 8.16%) (P = .024). The results of univariate analysis are shown in Table 2. In addition to minocycline administration, surgery on the left hemisphere (P = .040) and a smaller diameter of the recipient artery (P = .038) were significantly correlated with FND due to CHP. The age of the patients, sex, type of onset (hemorrhagic onset), and temporary occlusion time were not related to the development of FND due to CHP (P = .777, .234, .655, and .167, respectively). There was no
TABLE 2. Univariate Analysis of Focal Neurological Deficit Due to Cerebral Hyperperfusion After Extracranial-Intracranial Bypass Focal Neurological Deficit Due to Hyperperfusion Related Factors Patient age, y Male sex, no. (%) Left hemisphere, no. (%) Hemorrhagic onset, no. (%) Minocycline administration, no. (%) Diameter of recipient artery, mm Temporary occlusion time, min
Yes
No
P Value
34.5 2 (50) 4 (100) 0 (0) 0 (0) 0.775 19.8
40.4 25 (23.8) 50 (47.6) 5 (4.76) 60 (57.1) 0.989 22.6
.777 .233 .040 .655 .024 .038 .167
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significant difference in the systolic blood pressure 1 day after surgery between the minocycline-treated group (121.37 mm Hg) and non–minocycline group (121.33 mm Hg) (P = .583). The incidence of CHP detected by SPECT, both symptomatic and asymptomatic, was 33.3% (20/60) in the minocycline-treated group and 42.8% (21/49) in the non–minocycline group, and there was no statistical difference between both groups (P = .307). Multivariate Analysis We then performed multivariate analysis on factors that were significant in the univariate analysis. Because the age of patients and hemorrhagic-onset type were previously shown to be associated with the development of CHP, we also included these factors in this analysis. As shown in Table 3, multivariate analysis revealed that minocycline administration (P , .001), surgery on the left hemisphere (P = .003), and a smaller recipient artery diameter (P , .001) were significantly correlated with FND due to CHP (R2 = 0.7607).
REPRESENTATIVE CASE Adult Patient Perioperatively Managed Without Minocycline A 64-year-old woman presented with repeated TIA and right hand weakness and aphasia and had a diagnosis of MMD. Left carotid angiogram demonstrated stage 3 MMD according to Suzuki’s angiographic grading system (Figure 1B). A right carotid angiogram also demonstrated stage 4 MMD even though she had no ischemic sign of the right hemisphere (Figure 1A). Vertebral angiography demonstrated apparent stenosis of the left posterior cerebral artery. Preoperative 123I-IMP-SPECT revealed hemodynamic compromise on the left hemisphere. Therefore, she underwent STA-MCA anastomosis with EDMS on the left hemisphere. The recipient artery at the M4 segment of the frontal branch of the MCA was explored, and anastomosis was performed between the stump of the STA (1.3 mm in diameter) and the M4 segment (0.7 mm in diameter) supplying the left frontal lobe. The temporary occlusion time was 24 minutes. She was managed by
TABLE 3. Multivariate Analysis of Focal Neurological Deficit Due to Cerebral Hyperperfusion After Extracranial-Intracranial Bypassa Focal Neurological Deficit Due to Hyperperfusion Related Factors Patient age, y Left hemisphere, no. (%) Hemorrhagic onset, no. (%) Minocycline administration, no. (%) Diameter of recipient artery, mm
Yes
No
P Value
34.5 4 (100) 0 (0) 0 (0) 0.775
40.4 50 (47.6) 5 (4.76) 60 (57.1) 0.989
.739 .003 .247 ,.001 ,.001
a 2
R = 0.7607.
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prophylactic blood pressure lowering to less than 130 mm Hg systolic blood pressure (110-130 mm Hg) without minocycline administration. 123I-IMP-SPECT 1 day after surgery revealed an increase in CBF at the site of anastomosis, and she exhibited motor aphasia 2 days after surgery when CT scans revealed subarachnoid hemorrhage (Figure 1D), which was not evident 1 day after surgery (Figure 1C). Based on the diagnosis of symptomatic CHP, we reduced her blood pressure further and ceased antiplatelet agents to avoid the deleterious effect of CHP. From postoperative days 2 to 6, we attempted to control her systolic blood pressure at between 100 and 120 mm Hg, whereas her actual systolic blood pressure ranged between 81 and 128 mm Hg during this period. From 6 days after surgery, we controlled her systolic blood pressure at between 110 and 130 mm Hg. Repeat 123I-IMP-SPECT indicated prolonged CHP over 10 days (arrows in Figure 2A), and MRA demonstrated a thick high signal of the left STA (arrow in Figure 2B). However, cerebral infarction developed at the ipsilateral occipital lobe. Although her aphasia resolved gradually within 3 months, she permanently exhibited quadrant hemianopsia due to occipital lobe infarction (arrow in Figure 2C). Her TIA completely disappeared after surgery, and she did not experience any further cerebrovascular events during the 4-year follow-up period. She was independence in her activities of daily living, with a modified Rankin Scale score of 2.
DISCUSSION In the present study, we demonstrated for the first time that minocycline, a neuroprotective antibiotic with an inhibitory effect on MMP-9,22 may play a role in preventing FND due to CHP after EC-IC bypass for MMD. Based on our results, we could establish multidisciplinary strategy, including prophylactic blood pressure lowering with minocycline administration, to counteract CHP as a potential complication of EC-IC bypass for MMD (Figure 3). Role of Minocycline in Perioperative Management of EC-IC Bypass Minocycline, a semisynthetic tetracycline, has been clinically used as an antibiotic and anti-inflammatory drug. The neuroprotective potential of minocycline has been reported in animal models of cerebral ischemia.22,23 Minocycline was previously shown to reduce infarction size in rats due to the prevention of inflammatory reactions by suppressing microglial activation,22 down-regulating proinflammatory cytokines, and blocking MMP expression.21,23 Minocycline was shown to prevent reperfusionrelated intracerebral hemorrhage by blocking MMP-9 in mice.23 In addition to its anti-inflammatory effect, minocycline has a neuroprotective role as an antiapoptotic agent24 and antioxidant.25 Therefore, minocycline was considered to be highly effective in a clinical setting of ischemia-reperfusion injury because its potential role as an antioxidant and MMP inhibitor contributed to maintenance of the blood-brain barrier, which reduced the risk of vasogenic edema and hemorrhagic conversion.19,20 Because of the
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FIGURE 1. Representative case of a 64-year-old woman undergoing left superficial temporal artery–middle cerebral artery anastomosis with pial synangiosis, managed without minocycline. Preoperative right (A) and left (B) carotid angiograms demonstrated steno-occlusive changes at the terminal internal carotid arteries and an abnormal vascular network at the base of the brain. Computed tomography showed subarachnoid hemorrhage at the left sylvian cistern 2 days after surgery (D) that was not evident on postoperative day 1 (C).
higher expression of MMP-9 in patients with MMD,17,18 we hypothesized that the perioperative administration of minocycline for MMD patients could prevent surgical complications including both CHP and cerebral ischemia. The results of this study showed that FND due to CHP or ischemic complications developed in none of the patients managed by minocycline with strict blood pressure lowering. Incidence and Clinical Manifestation of Symptomatic CHP After EC-IC Bypass Symptomatic CPH after EC-IC bypass for atherosclerotic occlusive cerebrovascular disease has been considered rare and mostly presents with a mild F that resolved within 2 weeks.26,27 However, in contrast to atherosclerotic patients, increasing evidence suggests that CHP is the cause of transient neurological deterioration6-16 or delayed intracerebral hemorrhage28 during the acute stage after EC-IC bypass for MMD. The incidence of temporary neurological deterioration due to hyperperfusion was reported to be between 16.7% and 38.2%,7-9,11,13,14 when mild focal neurological signs were included. In this study, the incidence of FND due to CHP among all 86 patients undergoing 109 surgeries was as low as 3.67% (4/109) because we conducted prophylactic blood pressure lowering that was reported to reduce the risk of symptomatic CHP after EC-IC bypass for MMD.16 Although our series may include patients with a heterogeneous
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background, we prospectively controlled postoperative systolic blood pressure at between 110 and 130 mm Hg, based on our previous study in which blood pressure–dependent improvement of symptomatic hyperperfusion was observed at this threshold. Regarding the clinical presentation of CHP, transient FND that mimics an ischemic attack is a characteristic symptom among patients with MMD,7-9,11,13 unlike the symptom of patients undergoing carotid endarterectomy who commonly exhibit progressive headaches, ophthalmoplegia, and seizures.29,30 In this study, we focused on this characteristic symptom and investigated whether minocycline administration, in addition to prophylactic blood pressure lowering, could further reduce the risk of CHP. Interestingly, in no patients who were managed by minocycline with prophylactic blood pressure lowering did focal neurological signs develop due to CHP. Thus, we recommend a multidisciplinary approach for the perioperative management of MMD with prophylactic blood pressure lowering, minocycline administration, and the use of antiplatelet agents (Figure 3). Risk Factors of CHP After EC-IC Bypass for MMD Among MMD patients undergoing EC-IC bypass, adult patients have been shown to have a higher risk of postoperative CHP than that of pediatric patients.9,13 We reported, for the first time, that the incidence of transient neurological deterioration due to CHP, including mild focal neurological signs, was as high as 38.2%
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FIGURE 2. A, N-isopropyl-p-[123I]iodoamphetamine single-photon emission computed tomography 7 days after left superficial temporal artery–middle cerebral artery (STA-MCA) anastomosis in the same patient. A focal increase in cerebral flow was evident at the site of anastomosis (arrows in A). B, magnetic resonance angiography 7 days after left STA-MCA anastomosis, demonstrating STA-MCA bypass as a thick high signal sign (arrow in B). C, diffusion-weighted imaging 7 days after surgery demonstrating the development of cerebral infarction at the left occipital lobe (arrow) during intensive blood pressure lowering to prevent cerebral hyperperfusion.
among adult MMD patients who underwent direct EC-IC bypass7 and that the incidence of symptomatic CHP was significantly higher in adult patients than in pediatric patients.9 In addition to the age of patients, both the onset type of hemorrhagic presentation9 and increased preoperative cerebral blood volume13 were reported to be risk factors for CHP. This study provided new observations regarding the risk factors of CHP in MMD; both surgery on the left hemisphere and a smaller diameter of the recipient artery were found to be significant risk factors for FND due to CHP after EC-IC bypass for MMD. Although the age of patients did not correlate with CHP in this study, this could be due to the smaller number of pediatric patients in the study. Underlying Mechanism for the Occurrence of CHP in Patients With MMD The reason why MMD patients were at higher risk of CHP remains to be determined. A poorer network formation of pial
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arteries, leading to poorer hemodynamic distribution after revascularization surgery, may explain the higher risk of CHP in patients with MMD.8,10 Furthermore, intrinsic histopathological fragility of the peripheral pial artery, such as thinness of the medial layer and affected internal elastic lamina,31,32 may further support MMD patients being more vulnerable to a rapid increase in CBF in ischemic brains. Regarding the biomarkers related to maintenance of the blood-brain barrier, recent studies using the dura mater, arachnoid membrane, and serum obtained from patients with MMD demonstrated that the expression of vascular endothelial growth factor33 and MMP-9,17,18 both of which have a potential role in increasing the permeability of the blood-brain barrier, was significantly higher in MMD patients than in healthy control subjects. These findings raise the possibility that the increased expression of vascular endothelial growth factor and MMP-9 in patients with MMD may contribute, at least in part, to their vulnerability to CHP. This study demonstrated that
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CONCLUSION Among MMD patients undergoing STA-MCA anastomosis under the protocol of prophylactic blood pressure lowering during the perioperative period, the incidence of FND due to CHP was significantly lower in minocycline-treated patients than in patients not treated with minocycline. The administration of minocycline in combination with strict blood pressure control could represent secure and effective postoperative management for the prevention of symptomatic CHP after STA-MCA anastomosis for MMD. Disclosure FIGURE 3. Diagrammatic view of the multidisciplinary approach to cerebral hyperperfusion after superficial temporal artery–middle cerebral artery anastomosis in patients with moyamoya disease. Minocycline may not only have prevented neurological deterioration due to cerebral hyperperfusion by blocking matrix metalloproteinase-9, but also compensated for the deleterious effect of blood pressure lowering by protecting the contralateral and/or remote brain. BBB, blood-brain barrier; BP, blood pressure; MMP-9, matrix metalloproteinase 9; SBP, systolic blood pressure.
minocycline, an MMP-9 inhibitor,21 may play a role in preventing FND due to CHP, which suggested the involvement of MMPs in CHP after EC-IC bypass for MMD. Study Limitations First, the number of patients manifesting FND due to CHP was as small as 4 among 86 patients undergoing 109 surgeries, and each patient in the minocycline-treated and non-minocycline-treated groups may have heterogeneous backgrounds including different angioarchitecture, different comorbidities, different smoking status, and different preoperative cerebral hemodynamics. Thus, we do not completely rule out the possibility that heterogeneity of the patients’ background might have affected the results. Second, we could not include preoperative hemodynamic status as the associated factors with hyperperfusion to be analyzed in this study because we avoided SPECT with acetazolamide stress testing in high-risk patients with crescendo TIA or progressing stroke and some of the pediatric patients. Furthermore, preoperative CBF studies were performed at a variety of institutions under different conditions because most of our patients were referred from affiliated hospitals, and we avoid repeat CBF studies before surgery if the patients demonstrate apparent ischemic symptoms. For these reasons, we considered that our preoperative flow study data were not suitable for statistical analysis. Finally, we are not able to rule out the possibility that minocycline prevented CHP in this study by blocking a different pathway because we did not show decreased MMP-9 serum levels in each patient. Further studies on the temporal profiles of various biomarkers during the perioperative period in each patient managed with or without minocycline are necessary to address this important issue.
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The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.
REFERENCES 1. Suzuki J, Takaku A. Cerebrovascular “moyamoya” disease. Disease showing abnormal net-like vessels in base of brain. Arch Neurol. 1969;20(3):288-299. 2. Research Committee on the Pathology and treatment of Spontaneous Occlusion of the Circle of Willis; Health Labour Sciences Research Grant for Research on Measures for Intractable Diseases. Guidelines for diagnosis and treatment of moyamoya disease (Spontaneous occlusion of the circle of Willis). Neurol Med Chir (Tokyo). 2012;52(5):245-266. 3. Guzman R, Lee M, Achrol A, et al. Clinical outcome after 450 revascularization procedures for moyamoya disease. J Neurosurg. 2009;111(5):927-935. 4. Houkin K, Ishikawa T, Yoshimoto T, Abe H. Direct and indirect revascularization for moyamoya disease: surgical techniques and peri-operative complications. Clin Neurol Neurosurg. 1997;99(suppl 2):S142-S145. 5. Okada Y, Shima T, Nishida M, Yamane K, Yamada T, Yamanaka C. Effectiveness of superficial temporal artery-middle cerebral artery anastomosis in adult moyamoya disease: cerebral hemodynamics and clinical course in ischemic and hemorrhagic varieties. Stroke. 1998;29(3):625-630. 6. Furuya K, Kawahara N, Morita A, Momose T, Aoki S, Kirino T. Focal hyperperfusion after superficial temporal artery-middle cerebral artery anastomosis in a patient with moyamoya disease. Case report. J Neurosurg. 2004;100(1):128-132. 7. Fujimura M, Kaneta T, Mugikura S, Shimizu H, Tominaga T. Temporary neurologic deterioration due to cerebral hyperperfusion after superficial temporal artery-middle cerebral artery anastomosis in patients with adult-onset moyamoya disease. Surg Neurol. 2007;67(3):273-282. 8. Kim JE, Oh CW, Kwon OK, Park SQ, Kim SE, Kim YK. Transient hyperperfusion after superficial temporal artery/middle cerebral artery bypass surgery as a possible cause of postoperative transient neurological deterioration. Cerebrovasc Dis. 2008;25(6):580-586. 9. Fujimura M, Mugikura S, Kaneta T, Shimizu H, Tominaga T. Incidence and risk factors for symptomatic cerebral hyperperfusion after superficial temporal arterymiddle cerebral artery anastomosis in patients with moyamoya disease. Surg Neurol. 2009;71(4):442-447. 10. Nakagawa A, Fujimura M, Arafune T, Sakuma I, Tominaga T. Clinical implications of intraoperative infrared brain surface monitoring during superficial temporal artery-middle cerebral artery anastomosis in patients with moyamoya disease. J Neurosurg. 2009;111(6):1158-1164. 11. Fujimura M, Shimizu H, Inoue T, Mugikura S, Saito A, Tominaga T. Significance of focal cerebral hyperperfusion as a cause of transient neurologic deterioration after EC-IC bypass for moyamoya disease: comparative study with non-moyamoya patients using 123I-IMP-SPECT. Neurosurgery. 2011;68(4):957-965. 12. Pandey P, Steinberg GK. Neurosurgical advances in the treatment of moyamoya disease. Stroke. 2011;42(11):3304-3310. 13. Uchino H, Kuroda S, Hirata K, Shiga T, Houkin K, Tamaki N. Predictors and clinical features of postoperative hyperperfusion after surgical revascularization for moyamoya disease: a serial single photon emission CT/positron emission tomography study. Stroke. 2012;43(10):2610-2616. 14. Kaku Y, Iihara K, Nakajima N, et al. Cerebral blood flow and metabolism of hyperperfusion after cerebral revascularization in patients with moyamoya disease. J Cereb Blood Flow Metab. 2012;32(11):2066-2075.
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15. Morisawa H, Kawamata T, Kawashima A, et al. Hemodynamics and changes after STAMCA anastomosis in moyamoya disease and atherosclerotic cerebrovascular disease measured by micro-Doppler ultrasonography. Neurosurg Rev. 2013;36(3):411-419. 16. Fujimura M, Inoue T, Shimizu H, Saito A, Mugikura S, Tominaga T. Efficacy of prophylactic blood pressure lowering according to a standardized postoperative management protocol to prevent symptomatic cerebral hyperperfusion after direct revascularization surgery for moyamoya disease. Cerebrovasc Dis. 2012;33(5): 436-445. 17. Fujimura M, Watanabe M, Narisawa A, Shimizu H, Tominaga T. Increased expression of serum matrix metalloproteinase-9 in patients with moyamoya disease. Surg Neurol. 2009:72(5):476-480. 18. Kang HS, Kim JH, Phi JH, et al. Plasma matrix metalloproteinases, cytokines and angiogenic factors in moyamoya disease. J Neurol Neurosurg Psychiatry. 2010;81(6): 673-678. 19. Fujimura M, Gasche Y, Morita-Fujimura Y, Massengale J, Kawase M, Chan PH. Early appearance of activated matrix metalloproteinase-9 and blood-brain barrier disruption in mice after focal cerebral ischemia and reperfusion. Brain Res. 1999; 842(1):92-100. 20. Montaner J, Molina CA, Monasterio J, et al. Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation. 2003;107(4):598-603. 21. Yong VW, Wells J, Giuliani F, Casha S, Power C, Metz LM. The promise of minocycline in neurology. Lancet Neurol. 2004;3(12):744-751. 22. Yrjänheikki J, Tikka T, Keinänen R, Goldsteins G, Chan PH, Koistinaho J. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci U S A. 1999;96(23):13496-13500. 23. Maier CM, Hsieh L, Crandall T, Narasimhan P, Chan PH. Evaluating therapeutic targets for reperfusion-related brain hemorrhage. Ann Neurol. 2006;59(6):929-938. 24. Zhu S, Stavrovskaya IG, Drozda M, et al. Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature. 2002;417(6884):74-78. 25. Sakata H, Niizuma K, Yoshioka H, et al. Minocycline-preconditioned neural stem cells enhance neuroprotection after ischemic stroke in rats. J Neurosci. 2012;32 (10):3462-3473. 26. Heros RC, Scott RM, Ackerman RH, Conner ES. Temporary neurological deterioration after extracranial-intracranial bypass. Neurosurgery. 1984;15(2):178-185. 27. Yamaguchi K, Kawamata T, Kawashima A, Hori T, Okada Y: Incidence and predictive factors of cerebral hyperperfusion after extracranial-intracranial bypass for occlusive cerebrovascular diseases. Neurosurgery. 2010;67(6):1548-1554.
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28. Fujimura M, Shimizu H, Mugikura S, Tominaga T. Delayed intracerebral hemorrhage after superficial temporal artery-middle cerebral artery anastomosis in a patient with moyamoya disease: possible involvement of cerebral hyperperfusion and increased vascular permeability. Surg Neurol. 2009;71 (2):223-227. 29. Piepgras DG, Morgan MK, Sundt TM Jr, Yanagihara T, Mussman LM. Intracerebral hemorrhage after carotid endarterectomy. J Neurosurg. 1988;68(4): 532-536. 30. Solomon RA, Loftus CM, Quest DO, Correll JW. Incidence and etiology of intracerebral hemorrhage following carotid endarterectomy. J Neurosurg. 1986;64 (1):29-34. 31. Oka K, Yamashita M, Sadoshima S, Tanaka K. Cerebral haemorrhage in Moyamoya disease at autopsy. Virchows Arch A Pathol Anat Histol. 1981;392(3):247-261. 32. Takagi Y, Kikuta K, Nozaki K, Hashimoto N. Histological features of middle cerebral arteries from patients treated for Moyamoya disease. Neurol Med Chir (Tokyo). 2007;47(1):1-4. 33. Sakamoto S, Kiura Y, Yamasaki F, et al. Expression of vascular endothelial growth factor in dura matter of patients with moyamoya disease. Neurosurg Rev. 2008;31(1): 77-81.
COMMENT
T
he authors report a reduction in the incidence of symptomatic cerebral hyperperfusion after superficial temporal artery–middle cerebral artery bypass for moyamoya disease in a cohort treated with a protocol of minocycline administration and strict postoperative blood pressure (BP) control (0/60, 0%) compared with historical controls managed with only BP control (4/49, 8%). No adverse effects related to administration of minocycline were noted. The absolute number of events is small, even in the control group, and as a nonrandomized study with noncontemporaneous controls, definitive conclusions are limited. Nevertheless, these data provide intriguing preliminary support for the efficacy of a simple and seemingly safe therapy to reduce neurological complications after moyamoya disease surgery. Sepideh Amin-Hanjani Chicago, Illinois
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TOPIC
Minocycline Prevents Focal Neurological Deterioration Due to Cerebral Hyperperfusion After Extracranial-Intracranial Bypass for Moyamoya Disease Miki Fujimura, MD*‡ Kuniyasu Niizuma, MD* Takashi Inoue, MD‡ Kenichi Sato, MD* Hidenori Endo, MD* Hiroaki Shimizu, MD* Teiji Tominaga, MD* *Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan; ‡Department of Neurosurgery, National Hospital Organization, Sendai Medical Center, Sendai, Japan Correspondence: Miki Fujimura, MD, PhD, Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1.1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. E-mail: [email protected] Received, August 6, 2013. Accepted, October 25, 2013. Published Online, October 30, 2013. Copyright © 2013 by the Congress of Neurological Surgeons
BACKGROUND: Cerebral hyperperfusion (CHP) is a potential complication of superficial temporal artery–middle cerebral artery (STA-MCA) anastomosis for moyamoya disease (MMD), and optimal postoperative management has not yet been established. Minocycline, a neuroprotective antibiotic agent, plays a role in blocking matrix metalloproteinase 9 (MMP-9), which contributes to edema formation and hemorrhagic conversion after cerebral ischemia-reperfusion. Patients with MMD have been shown to have increased serum MMP-9 levels. OBJECTIVE: To examine the effect of minocycline on the prevention of postoperative CHP after STA-MCA anastomosis for MMD. METHODS: N-isopropyl-p-[123I]iodoamphetamine single-photon emission computed tomography was performed 1 and 7 days after STA-MCA anastomosis on 109 hemispheres in 86 consecutive patients with MMD (ages, 9-69 years; mean, 37.2 years). Postoperative systolic blood pressure was strictly maintained at lower than 130 mm Hg in all 109 surgeries. The most 60 recent hemispheres were managed by the intraoperative and postoperative intravenous administration of minocycline hydrochloride (200 mg/d). The incidence of focal neurological deterioration (FND) due to CHP was then compared with that in 36 patients undergoing 49 surgeries managed without minocycline. RESULTS: FND due to CHP was observed in 4 operated hemispheres in patients treated without minocycline (4/49, 8.16%), and in none in the minocycline-treated group (0/60) (P = .0241). Multivariate analysis revealed that minocycline administration (P , .001), surgery on the left hemisphere (P = .031), and a smaller recipient artery diameter (P , .001) significantly correlated with FND due to CHP. CONCLUSION: The administration of minocycline with strict blood pressure control may represent secure and effective postoperative management to prevent symptomatic CHP after STA-MCA anastomosis for MMD. KEY WORDS: Cerebral hyperperfusion, Extracranial-intracranial bypass, Minocycline hydrochloride, Moyamoya disease, Surgical complication Neurosurgery 74:163–170, 2014
DOI: 10.1227/NEU.0000000000000238
ABBREVIATIONS: CBF, cerebral blood flow; CHP, cerebral hyperperfusion; EC-IC, extracranialintracranial; EDMS, encephaloduromyosynangiosis; FND, focal neurological deterioration; 123I-IMPSPECT, N-isopropyl-p-[123I]iodoamphetamine singlephoton emission computed tomography; MCA, middle cerebral artery; MMD, moyamoya disease; MMP-9, matrix metalloproteinase 9; MRA, magnetic resonance angiography; SPECT, single-photon emission computed tomography; STA-MCA, superficial temporal artery–middle cerebral artery
NEUROSURGERY
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M
oyamoya disease (MMD) is a chronic, occlusive cerebrovascular disease of unknown etiology characterized by bilateral steno-occlusive changes at the terminal portion of the internal carotid artery and an abnormal vascular network at the base of the brain.1,2 The extracranial-intracranial (EC-IC) bypass such as superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis is generally used as the standard surgical treatment for MMD to prevent cerebral ischemic attacks.2-5
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Despite its favorable long-term outcome, increasing evidence suggests that focal cerebral hyperperfusion (CHP) is a cause of transient focal neurological deterioration (FND)6-15; however, optimal management remains undetermined. We previously showed that prophylactic blood pressure lowering during the early perioperative period reduced the risk of symptomatic CHP in patients with MMD,16 whereas excessive blood pressure lowering is still controversial because of the risk of ischemic complications at contralateral and/or remote areas. The expression of extracellular matrix proteins including matrix metalloproteinase 9 (MMP-9), which may play a role in degrading the endothelial basal lamina, an important structure in the bloodbrain barrier, by digesting type IV collagen, was shown to be higher in patients with MMD.17,18 MMP-9 is known to participate in edema formation and hemorrhagic conversion after cerebral ischemia-reperfusion injury.19,20 Because of the higher incidence of postoperative CHP in moyamoya patients than in atherosclerotic patients,11 it is conceivable that the increased expression of MMP-9 may contribute in part to CHP in patients with MMD. Because minocycline hydrochloride may play a role in blocking MMP-921 and is also known to have a neuroprotective effect against ischemic brain injury,22,23 we sought to determine whether the effect of minocycline, in addition to prophylactic blood pressure lowering, further reduced the risk of postoperative CHP after STA-MCA anastomosis for MMD.
PATIENTS AND METHODS Inclusion Criteria of Patients The correlation between postoperative changes in cerebral blood flow (CBF) and clinical course was investigated in 86 consecutive patients with MMD (male/female = 24/62; 9-69 years of age; mean, 37.2 years) surgically treated in 109 hemispheres by the same surgeon (M.F.) between January 2008 and June 2013. Inclusion criteria of this study, which corresponded to our surgical indications for STA-MCA anastomosis,11 included all of the following: the presence of ischemic symptoms (minor completed stroke and/or transient ischemic attack [TIA]), apparent hemodynamic compromise on single-photon emission computed tomography (SPECT) as defined in the following, independent activity of daily living (modified Rankin Scale scores of 0-2), and the absence of major cerebral infarction that exceeds the vascular territory of 1 major branch of the middle cerebral artery (MCA). All hemispheres that did not match these criteria were excluded from surgery. This study included 5 patients with a history of hemorrhage in whom 5 hemispheres were operated on. All 5 patients simultaneously had TIA or cerebral infarction on the affected hemispheres before surgery, which matched our indication for surgery. Preoperative CBF was quantified by the autoradiographic method in most cases, and CBF in each subregion was automatically calculated by 3-dimensional stereotactic region of interest template) software (version 2) provided by Daiichi Radio-Isotope (Tokyo, Japan) using N-isopropylp-[123I]iodoamphetamine single-photon emission computed tomography (123I-IMP-SPECT).11 The cerebral perfusion reserve capacity was quantified by the administration of acetazolamide. When CBF at rest was less than 80% of normal CBF (42 mL/100 g/min) and/or reactivity to acetazolamide was less than 10%, we regarded the CBF state as hemodynamic compromise. To avoid ischemic complications during examination,
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patients with crescendo TIA did not participate in the preoperative quantitative CBF study, only qualitative 123I-IMP-SPECT without acetazolamide stress testing. Most of the pediatric patients did not participate in preoperative 123I-IMP-SPECT with acetazolamide stress testing to avoid ischemic complications. One adult patient with progressing stroke underwent qualitative 123I-IMP-SPECT without acetazolamide stress testing only before surgery. Once hemodynamic compromise was confirmed, patients underwent revascularization surgery. All patients underwent STA-MCA (M4) anastomosis with encephaloduromyosynangiosis (EDMS).11 Patients were maintained under the conditions of normovolemia and normocapnia, whereas intraoperative systolic blood pressure was strictly maintained at less than 130 mm Hg during surgery by intravenous anesthesia using propofol.16 Craniotomy was performed around the sylvian fissure end, approximately 8 cm in diameter, and the stump of STA was anastomosed to the M4 segment of the MCA, which was followed by EDMS. To avoid postoperative compression of the brain surface by the swollen temporal muscle used for EDMS, we drilled out the inner layer of the bone flap and made a relatively wide bone window at the side of the EDMS graft insertion. All patients satisfied the diagnostic criteria of the Research Committee on Spontaneous Occlusion of the Circle of Willis of the Ministry of Health, Labor, and Welfare, Japan,2 except for 4 patients with “probable MMD” showing unilateral involvement.
Postoperative CBF Measurement and Diagnosis of Hyperperfusion CBF was routinely measured by 123I-IMP-SPECT 1 and 7 days after surgery in all patients. Postoperative computed tomography scans were routinely performed immediately after surgery and 1 day after surgery in all cases. Magnetic resonance imaging (MRI), 1.5 or 3T, and magnetic resonance angiography (MRA) were routinely performed within 3 days of surgery. MRI included diffusion-weighted images, T2-weighted images, and T2*-weighted images in all cases. Fluid-attenuated inversion recovery was also performed in most cases. The diagnostic criteria for symptomatic CHP11,16 included all of the following: (1) the presence of a significant focal increase in CBF, which was confined to the vascular territory of 1 major branch of the MCA at the site of the anastomosis, which was responsible for the apparent focal neurological signs; (2) apparent visualization of the STA-MCA bypass by MRA and the absence of any ischemic changes on diffusion-weighted images; and (3) the absence of other pathologies such as compression of the brain surface by the temporal muscle inserted for indirect pial synangiosis, ischemic attack, venous infarction, and CBF increases secondary to seizure. In addition to these items, blood pressure–dependent aggravation of symptoms and/or the amelioration of symptoms by blood pressure lowering clinically confirmed the diagnosis of symptomatic CHP. The occurrence of symptomatic CHP after revascularization surgery was evaluated by 123I-IMP-SPECT in the acute stage. We investigated the correlation between postoperative CBF changes and FND due to CHP in the 2 groups.
Postoperative Management All 86 patients with 109 hemispheres operated on were prospectively subjected to prophylactic intensive blood pressure control (,130 mm Hg systolic blood pressure) according to the standardized postoperative management protocol to prevent symptomatic CHP using a 1 to 10 mg/h continuous intravenous drip infusion of nicardipine hydrochloride, as previously described.16 Among them, 36 patients undergoing
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MINOCYCLINE TO PREVENT CEREBRAL HYPERPERFUSION
revascularization surgery for 49 hemispheres were managed by the routine prophylactic use of ampicillin-sulbactam (3.0 g/d) for 4 days, between January 2008 and July 2010. During the most recent period (between August 2010 and June 2013), 50 patients underwent revascularization surgery for 60 hemispheres and were managed by the intraoperative and postoperative intravenous administration of minocycline hydrochloride (200 mg/d) instead of ampicillin-sulbactam until 4 days after surgery to avoid the deleterious effects of CHP and reduce the potential risk of cerebral ischemia at remote areas. The protocol for the use of minocycline hydrochloride was approved by the Ethics Committee in our institution. Patients in whom symptomatic CHP developed underwent further blood pressure lowering. To avoid the unfavorable effect of intensive blood pressure lowering on the contralateral hemisphere and/or ipsilateral remote areas, we sought to maintain systolic blood pressure between 110 and 130 mm Hg, and we routinely administered antiplatelet agents (aspirin 100 mg/d or cilostazol 200 mg/d) starting the day after surgery in both periods. Based on the temporal profile of 123I-IMP-SPECT and MRI/ MRA findings, we gradually allowed a return to normotensive conditions within 7 to 10 days after surgery. If 123I-IMP-SPECT performed 1 day after surgery suggested focal hyperperfusion, we maintained strict blood pressure control at between 110 and 130 mm Hg or between 100 and 120 mm Hg, according to the severity of hyperperfusion, for 7 to 14 days after revascularization surgery.16
Statistical Analysis The incidence of FND due to CHP was compared between the minocycline-treated group and non–minocycline-treated group using logistic regression analysis. Correlations between focal neurological signs due to CHP and others factors including patient age, sex, side of the hemisphere operated on, type of onset (hemorrhagic onset), diameter of the recipient artery, and temporary occlusion time were also analyzed using a univariate logistic regression model. Multivariate statistical analysis of factors related to the development of symptomatic CHP, including the administration of minocycline, was performed using a logistic regression model. Systolic blood pressure 1 day after surgery was compared between the 2 groups by the Student t test. The incidence of CHP detected by SPECT, both symptomatic and asymptomatic, was also compared between the 2 groups by the x2 test.
RESULTS Overall Results Among the 86 consecutive patients with 109 surgeries, 4 patients (4 hemispheres, 3.67% of 109 operated hemispheres) exhibited temporary FND due to postoperative focal CHP 2 to 14 days after surgery (Table 1). All 4 patients were treated without minocycline. Postoperative MRI/MRA showed no ischemic changes, and the thick high signal of STA on the hemisphere operated on was evident in all 4 hemispheres. Postoperative SPECT revealed a significant increase in CBF at the sites of anastomosis in all 4 hemispheres. The anatomic location and temporal profile of hyperperfusion were consistent with the transient focal neurological signs in these 4 patients. The symptoms observed in all 4 cases fluctuated in a blood pressure–dependent manner, which further supported the diagnosis of symptomatic hyperperfusion. The symptoms of hyperperfusion were relieved by further blood
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TABLE 1. Incidence of Focal Neurological Deficit Due to Hyperperfusion After Extracranial-Intracranial Bypass
Hemisphere, no. (patients, no.) Age, y, range (mean) Male/female, no. Left/right, no. Focal neurological deficit due to hyperperfusion, no. (%) a
Minocycline Group
Non-Minocycline Group
60 (50) 10-66 (39.4) 11/39 30/30 0/60 (0)a
49 (36) 9-69 (35.9) 13/23 24/25 4/49 (8.16)
Significantly lower (P = .024).
pressure lowering with the free radical scavenger edaravone (Mitsubishi Pharma Co, Tokyo, Japan), although in 1 patient in the non–minocycline-treated group cerebral infarction in the ipsilateral occipital lobe developed during blood pressure lowering, which has been described as the representative case. FND due to CHP developed in none of the minocycline-treated patients. No adverse effect was reported for minocycline after 60 surgeries perioperatively managed with minocycline. Comparison of the Minocycline-Treated Group and Non–Minocycline-Treated Group Univariate Analysis As shown in Table 1, the incidence of FND due to CHP was significantly lower in minocycline-treated patients (0/60, 0%) than in patients treated without minocycline (4/49, 8.16%) (P = .024). The results of univariate analysis are shown in Table 2. In addition to minocycline administration, surgery on the left hemisphere (P = .040) and a smaller diameter of the recipient artery (P = .038) were significantly correlated with FND due to CHP. The age of the patients, sex, type of onset (hemorrhagic onset), and temporary occlusion time were not related to the development of FND due to CHP (P = .777, .234, .655, and .167, respectively). There was no
TABLE 2. Univariate Analysis of Focal Neurological Deficit Due to Cerebral Hyperperfusion After Extracranial-Intracranial Bypass Focal Neurological Deficit Due to Hyperperfusion Related Factors Patient age, y Male sex, no. (%) Left hemisphere, no. (%) Hemorrhagic onset, no. (%) Minocycline administration, no. (%) Diameter of recipient artery, mm Temporary occlusion time, min
Yes
No
P Value
34.5 2 (50) 4 (100) 0 (0) 0 (0) 0.775 19.8
40.4 25 (23.8) 50 (47.6) 5 (4.76) 60 (57.1) 0.989 22.6
.777 .233 .040 .655 .024 .038 .167
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significant difference in the systolic blood pressure 1 day after surgery between the minocycline-treated group (121.37 mm Hg) and non–minocycline group (121.33 mm Hg) (P = .583). The incidence of CHP detected by SPECT, both symptomatic and asymptomatic, was 33.3% (20/60) in the minocycline-treated group and 42.8% (21/49) in the non–minocycline group, and there was no statistical difference between both groups (P = .307). Multivariate Analysis We then performed multivariate analysis on factors that were significant in the univariate analysis. Because the age of patients and hemorrhagic-onset type were previously shown to be associated with the development of CHP, we also included these factors in this analysis. As shown in Table 3, multivariate analysis revealed that minocycline administration (P , .001), surgery on the left hemisphere (P = .003), and a smaller recipient artery diameter (P , .001) were significantly correlated with FND due to CHP (R2 = 0.7607).
REPRESENTATIVE CASE Adult Patient Perioperatively Managed Without Minocycline A 64-year-old woman presented with repeated TIA and right hand weakness and aphasia and had a diagnosis of MMD. Left carotid angiogram demonstrated stage 3 MMD according to Suzuki’s angiographic grading system (Figure 1B). A right carotid angiogram also demonstrated stage 4 MMD even though she had no ischemic sign of the right hemisphere (Figure 1A). Vertebral angiography demonstrated apparent stenosis of the left posterior cerebral artery. Preoperative 123I-IMP-SPECT revealed hemodynamic compromise on the left hemisphere. Therefore, she underwent STA-MCA anastomosis with EDMS on the left hemisphere. The recipient artery at the M4 segment of the frontal branch of the MCA was explored, and anastomosis was performed between the stump of the STA (1.3 mm in diameter) and the M4 segment (0.7 mm in diameter) supplying the left frontal lobe. The temporary occlusion time was 24 minutes. She was managed by
TABLE 3. Multivariate Analysis of Focal Neurological Deficit Due to Cerebral Hyperperfusion After Extracranial-Intracranial Bypassa Focal Neurological Deficit Due to Hyperperfusion Related Factors Patient age, y Left hemisphere, no. (%) Hemorrhagic onset, no. (%) Minocycline administration, no. (%) Diameter of recipient artery, mm
Yes
No
P Value
34.5 4 (100) 0 (0) 0 (0) 0.775
40.4 50 (47.6) 5 (4.76) 60 (57.1) 0.989
.739 .003 .247 ,.001 ,.001
a 2
R = 0.7607.
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prophylactic blood pressure lowering to less than 130 mm Hg systolic blood pressure (110-130 mm Hg) without minocycline administration. 123I-IMP-SPECT 1 day after surgery revealed an increase in CBF at the site of anastomosis, and she exhibited motor aphasia 2 days after surgery when CT scans revealed subarachnoid hemorrhage (Figure 1D), which was not evident 1 day after surgery (Figure 1C). Based on the diagnosis of symptomatic CHP, we reduced her blood pressure further and ceased antiplatelet agents to avoid the deleterious effect of CHP. From postoperative days 2 to 6, we attempted to control her systolic blood pressure at between 100 and 120 mm Hg, whereas her actual systolic blood pressure ranged between 81 and 128 mm Hg during this period. From 6 days after surgery, we controlled her systolic blood pressure at between 110 and 130 mm Hg. Repeat 123I-IMP-SPECT indicated prolonged CHP over 10 days (arrows in Figure 2A), and MRA demonstrated a thick high signal of the left STA (arrow in Figure 2B). However, cerebral infarction developed at the ipsilateral occipital lobe. Although her aphasia resolved gradually within 3 months, she permanently exhibited quadrant hemianopsia due to occipital lobe infarction (arrow in Figure 2C). Her TIA completely disappeared after surgery, and she did not experience any further cerebrovascular events during the 4-year follow-up period. She was independence in her activities of daily living, with a modified Rankin Scale score of 2.
DISCUSSION In the present study, we demonstrated for the first time that minocycline, a neuroprotective antibiotic with an inhibitory effect on MMP-9,22 may play a role in preventing FND due to CHP after EC-IC bypass for MMD. Based on our results, we could establish multidisciplinary strategy, including prophylactic blood pressure lowering with minocycline administration, to counteract CHP as a potential complication of EC-IC bypass for MMD (Figure 3). Role of Minocycline in Perioperative Management of EC-IC Bypass Minocycline, a semisynthetic tetracycline, has been clinically used as an antibiotic and anti-inflammatory drug. The neuroprotective potential of minocycline has been reported in animal models of cerebral ischemia.22,23 Minocycline was previously shown to reduce infarction size in rats due to the prevention of inflammatory reactions by suppressing microglial activation,22 down-regulating proinflammatory cytokines, and blocking MMP expression.21,23 Minocycline was shown to prevent reperfusionrelated intracerebral hemorrhage by blocking MMP-9 in mice.23 In addition to its anti-inflammatory effect, minocycline has a neuroprotective role as an antiapoptotic agent24 and antioxidant.25 Therefore, minocycline was considered to be highly effective in a clinical setting of ischemia-reperfusion injury because its potential role as an antioxidant and MMP inhibitor contributed to maintenance of the blood-brain barrier, which reduced the risk of vasogenic edema and hemorrhagic conversion.19,20 Because of the
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FIGURE 1. Representative case of a 64-year-old woman undergoing left superficial temporal artery–middle cerebral artery anastomosis with pial synangiosis, managed without minocycline. Preoperative right (A) and left (B) carotid angiograms demonstrated steno-occlusive changes at the terminal internal carotid arteries and an abnormal vascular network at the base of the brain. Computed tomography showed subarachnoid hemorrhage at the left sylvian cistern 2 days after surgery (D) that was not evident on postoperative day 1 (C).
higher expression of MMP-9 in patients with MMD,17,18 we hypothesized that the perioperative administration of minocycline for MMD patients could prevent surgical complications including both CHP and cerebral ischemia. The results of this study showed that FND due to CHP or ischemic complications developed in none of the patients managed by minocycline with strict blood pressure lowering. Incidence and Clinical Manifestation of Symptomatic CHP After EC-IC Bypass Symptomatic CPH after EC-IC bypass for atherosclerotic occlusive cerebrovascular disease has been considered rare and mostly presents with a mild F that resolved within 2 weeks.26,27 However, in contrast to atherosclerotic patients, increasing evidence suggests that CHP is the cause of transient neurological deterioration6-16 or delayed intracerebral hemorrhage28 during the acute stage after EC-IC bypass for MMD. The incidence of temporary neurological deterioration due to hyperperfusion was reported to be between 16.7% and 38.2%,7-9,11,13,14 when mild focal neurological signs were included. In this study, the incidence of FND due to CHP among all 86 patients undergoing 109 surgeries was as low as 3.67% (4/109) because we conducted prophylactic blood pressure lowering that was reported to reduce the risk of symptomatic CHP after EC-IC bypass for MMD.16 Although our series may include patients with a heterogeneous
NEUROSURGERY
background, we prospectively controlled postoperative systolic blood pressure at between 110 and 130 mm Hg, based on our previous study in which blood pressure–dependent improvement of symptomatic hyperperfusion was observed at this threshold. Regarding the clinical presentation of CHP, transient FND that mimics an ischemic attack is a characteristic symptom among patients with MMD,7-9,11,13 unlike the symptom of patients undergoing carotid endarterectomy who commonly exhibit progressive headaches, ophthalmoplegia, and seizures.29,30 In this study, we focused on this characteristic symptom and investigated whether minocycline administration, in addition to prophylactic blood pressure lowering, could further reduce the risk of CHP. Interestingly, in no patients who were managed by minocycline with prophylactic blood pressure lowering did focal neurological signs develop due to CHP. Thus, we recommend a multidisciplinary approach for the perioperative management of MMD with prophylactic blood pressure lowering, minocycline administration, and the use of antiplatelet agents (Figure 3). Risk Factors of CHP After EC-IC Bypass for MMD Among MMD patients undergoing EC-IC bypass, adult patients have been shown to have a higher risk of postoperative CHP than that of pediatric patients.9,13 We reported, for the first time, that the incidence of transient neurological deterioration due to CHP, including mild focal neurological signs, was as high as 38.2%
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FIGURE 2. A, N-isopropyl-p-[123I]iodoamphetamine single-photon emission computed tomography 7 days after left superficial temporal artery–middle cerebral artery (STA-MCA) anastomosis in the same patient. A focal increase in cerebral flow was evident at the site of anastomosis (arrows in A). B, magnetic resonance angiography 7 days after left STA-MCA anastomosis, demonstrating STA-MCA bypass as a thick high signal sign (arrow in B). C, diffusion-weighted imaging 7 days after surgery demonstrating the development of cerebral infarction at the left occipital lobe (arrow) during intensive blood pressure lowering to prevent cerebral hyperperfusion.
among adult MMD patients who underwent direct EC-IC bypass7 and that the incidence of symptomatic CHP was significantly higher in adult patients than in pediatric patients.9 In addition to the age of patients, both the onset type of hemorrhagic presentation9 and increased preoperative cerebral blood volume13 were reported to be risk factors for CHP. This study provided new observations regarding the risk factors of CHP in MMD; both surgery on the left hemisphere and a smaller diameter of the recipient artery were found to be significant risk factors for FND due to CHP after EC-IC bypass for MMD. Although the age of patients did not correlate with CHP in this study, this could be due to the smaller number of pediatric patients in the study. Underlying Mechanism for the Occurrence of CHP in Patients With MMD The reason why MMD patients were at higher risk of CHP remains to be determined. A poorer network formation of pial
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arteries, leading to poorer hemodynamic distribution after revascularization surgery, may explain the higher risk of CHP in patients with MMD.8,10 Furthermore, intrinsic histopathological fragility of the peripheral pial artery, such as thinness of the medial layer and affected internal elastic lamina,31,32 may further support MMD patients being more vulnerable to a rapid increase in CBF in ischemic brains. Regarding the biomarkers related to maintenance of the blood-brain barrier, recent studies using the dura mater, arachnoid membrane, and serum obtained from patients with MMD demonstrated that the expression of vascular endothelial growth factor33 and MMP-9,17,18 both of which have a potential role in increasing the permeability of the blood-brain barrier, was significantly higher in MMD patients than in healthy control subjects. These findings raise the possibility that the increased expression of vascular endothelial growth factor and MMP-9 in patients with MMD may contribute, at least in part, to their vulnerability to CHP. This study demonstrated that
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MINOCYCLINE TO PREVENT CEREBRAL HYPERPERFUSION
CONCLUSION Among MMD patients undergoing STA-MCA anastomosis under the protocol of prophylactic blood pressure lowering during the perioperative period, the incidence of FND due to CHP was significantly lower in minocycline-treated patients than in patients not treated with minocycline. The administration of minocycline in combination with strict blood pressure control could represent secure and effective postoperative management for the prevention of symptomatic CHP after STA-MCA anastomosis for MMD. Disclosure FIGURE 3. Diagrammatic view of the multidisciplinary approach to cerebral hyperperfusion after superficial temporal artery–middle cerebral artery anastomosis in patients with moyamoya disease. Minocycline may not only have prevented neurological deterioration due to cerebral hyperperfusion by blocking matrix metalloproteinase-9, but also compensated for the deleterious effect of blood pressure lowering by protecting the contralateral and/or remote brain. BBB, blood-brain barrier; BP, blood pressure; MMP-9, matrix metalloproteinase 9; SBP, systolic blood pressure.
minocycline, an MMP-9 inhibitor,21 may play a role in preventing FND due to CHP, which suggested the involvement of MMPs in CHP after EC-IC bypass for MMD. Study Limitations First, the number of patients manifesting FND due to CHP was as small as 4 among 86 patients undergoing 109 surgeries, and each patient in the minocycline-treated and non-minocycline-treated groups may have heterogeneous backgrounds including different angioarchitecture, different comorbidities, different smoking status, and different preoperative cerebral hemodynamics. Thus, we do not completely rule out the possibility that heterogeneity of the patients’ background might have affected the results. Second, we could not include preoperative hemodynamic status as the associated factors with hyperperfusion to be analyzed in this study because we avoided SPECT with acetazolamide stress testing in high-risk patients with crescendo TIA or progressing stroke and some of the pediatric patients. Furthermore, preoperative CBF studies were performed at a variety of institutions under different conditions because most of our patients were referred from affiliated hospitals, and we avoid repeat CBF studies before surgery if the patients demonstrate apparent ischemic symptoms. For these reasons, we considered that our preoperative flow study data were not suitable for statistical analysis. Finally, we are not able to rule out the possibility that minocycline prevented CHP in this study by blocking a different pathway because we did not show decreased MMP-9 serum levels in each patient. Further studies on the temporal profiles of various biomarkers during the perioperative period in each patient managed with or without minocycline are necessary to address this important issue.
NEUROSURGERY
The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.
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COMMENT
T
he authors report a reduction in the incidence of symptomatic cerebral hyperperfusion after superficial temporal artery–middle cerebral artery bypass for moyamoya disease in a cohort treated with a protocol of minocycline administration and strict postoperative blood pressure (BP) control (0/60, 0%) compared with historical controls managed with only BP control (4/49, 8%). No adverse effects related to administration of minocycline were noted. The absolute number of events is small, even in the control group, and as a nonrandomized study with noncontemporaneous controls, definitive conclusions are limited. Nevertheless, these data provide intriguing preliminary support for the efficacy of a simple and seemingly safe therapy to reduce neurological complications after moyamoya disease surgery. Sepideh Amin-Hanjani Chicago, Illinois
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